Publications by authors named "Ian R Jones"

37 Publications

Parallel characterization of cis-regulatory elements for multiple genes using CRISPRpath.

Sci Adv 2021 Sep 15;7(38):eabi4360. Epub 2021 Sep 15.

Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.

[Figure: see text].
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http://dx.doi.org/10.1126/sciadv.abi4360DOI Listing
September 2021

Age and sex-related variability in the presentation of generalized anxiety and depression symptoms.

Depress Anxiety 2021 Sep 8. Epub 2021 Sep 8.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, Denmark Hill, Camberwell, London, UK.

Background: Generalized anxiety and depression are extremely prevalent and debilitating. There is evidence for age and sex variability in symptoms of depression, but despite comorbidity it is unclear whether this extends to anxiety symptomatology. Studies using questionnaire sum scores typically fail to address this phenotypic complexity.

Method: We conducted exploratory and confirmatory factor analyses on Generalized Anxiety Disorder (GAD-7) and Patient Health Questionnaire (PHQ-9) items to identify latent factors of anxiety and depression in participants from the Genetic Links to Anxiety and Depression Study (N = 35,637; 16-93 years). We assessed age- and sex-related variability in latent factors and individual symptoms using multiple logistic regression.

Results: Four factors of mood, worry, motor, and somatic symptoms were identified (comparative fit index [CFI] = 0.99, Tucker-Lewis Index [TLI] = 0.99, root mean square error of approximation [RMSEA] = 0.07, standardized root mean square residuals [SRMR] = 0.04). Symptoms of irritability (odds ratio [OR] = 0.81) were most strongly associated with younger age, and sleep change (OR = 1.14) with older age. Males were more likely to report mood and motor symptoms (p < .001) and females to report somatic symptoms (p < .001).

Conclusion: Significant age and sex variability suggest that classic diagnostic criteria reflect the presentation most commonly seen in younger males. This study provides avenues for diagnostic adaptation and factor-specific interventions.
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http://dx.doi.org/10.1002/da.23213DOI Listing
September 2021

Cell-type-specific 3D epigenomes in the developing human cortex.

Nature 2020 11 14;587(7835):644-649. Epub 2020 Oct 14.

Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.

Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone. Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.
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http://dx.doi.org/10.1038/s41586-020-2825-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704572PMC
November 2020

Promotion of Healthy Aging Within a Community Center Through Behavior Change: Health and Fitness Findings From the AgeWell Pilot Randomized Controlled Trial.

J Aging Phys Act 2020 08 11;29(1):80-88. Epub 2020 Aug 11.

The purpose of this randomized controlled trial was to determine if behavior change through individual goal setting (GS) could promote healthy aging, including health and fitness benefits in older adults who attended a community "AgeWell" Center for 12 months. Seventy-five older adults were randomly allocated to either a control or a GS group. Health outcomes were measured at baseline and after 12 months of the participants' having access to the exception of Agewell Center facilities. The findings demonstrate that participation in the Center in itself was beneficial, with improved body composition and reduced cardiovascular risk in both groups (p < .05), and that this kind of community-based resource offers valuable potential for promoting protective behaviors and reducing health risk. However, a specific focus on identifying individual behavior change goals was required in order to achieve increased activity engagement (p < .05) and to bring about more substantial improvements in a range of health, diet, and physical function measures (p < .05).
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http://dx.doi.org/10.1123/japa.2019-0396DOI Listing
August 2020

A meta-analysis comparing cognitive function across the mood/psychosis diagnostic spectrum.

Psychol Med 2020 Jun 22:1-9. Epub 2020 Jun 22.

Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK.

Background: The nature and degree of cognitive impairments in schizoaffective disorder is not well established. The aim of this meta-analysis was to characterise cognitive functioning in schizoaffective disorder and compare it with cognition in schizophrenia and bipolar disorder. Schizoaffective disorder was considered both as a single category and as its two diagnostic subtypes, bipolar and depressive disorder.

Methods: Following a thorough literature search (468 records identified), we included 31 studies with a total of 1685 participants with schizoaffective disorder, 3357 with schizophrenia and 1095 with bipolar disorder. Meta-analyses were conducted for seven cognitive variables comparing performance between participants with schizoaffective disorder and schizophrenia, and between schizoaffective disorder and bipolar disorder.

Results: Participants with schizoaffective disorder performed worse than those with bipolar disorder (g = -0.30) and better than those with schizophrenia (g = 0.17). Meta-analyses of the subtypes of schizoaffective disorder showed cognitive impairments in participants with the depressive subtype are closer in severity to those seen in participants with schizophrenia (g = 0.08), whereas those with the bipolar subtype were more impaired than those with bipolar disorder (g = -0.23) and less impaired than those with schizophrenia (g = 0.29). Participants with the depressive subtype had worse performance than those with the bipolar subtype but this was not significant (g = 0.25, p = 0.05).

Conclusion: Cognitive impairments increase in severity from bipolar disorder to schizoaffective disorder to schizophrenia. Differences between the subtypes of schizoaffective disorder suggest combining the subtypes of schizoaffective disorder may obscure a study's results and hamper efforts to understand the relationship between this disorder and schizophrenia or bipolar disorder.
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http://dx.doi.org/10.1017/S0033291720002020DOI Listing
June 2020

Factors associated with self- and informant ratings of quality of life, well-being and life satisfaction in people with mild-to-moderate dementia: results from the Improving the experience of Dementia and Enhancing Active Life programme.

Age Ageing 2020 04;49(3):446-452

REACH: The Centre for Research in Ageing and Cognitive Health, University of Exeter Medical School and College of Life and Environment Sciences, Exeter, UK.

Background: a large number of studies have explored factors related to self- and informant ratings of quality of life in people with dementia, but many studies have had relatively small sample sizes and mainly focused on health conditions and dementia symptoms. The aim of this study is to compare self- and informant-rated quality of life, life satisfaction and well-being, and investigate the relationships of the two different rating methods with various social, psychological and health factors, using a large cohort study of community-dwelling people with dementia and carers in Great Britain.

Methods: this study included 1,283 dyads of people with mild-to-moderate dementia and their primary carers in the Improving the experience of Dementia and Enhancing Active Life study. Multivariate modelling was used to investigate associations of self- and informant-rated quality of life, life satisfaction and well-being with factors in five domains: psychological characteristics and health; social location; capitals, assets and resources; physical fitness and health; and managing everyday life with dementia.

Results: people with dementia rated their quality of life, life satisfaction and well-being more highly than did the informants. Despite these differences, the two approaches had similar relationships with social, psychological and physical health factors in the five domains.

Conclusion: although self- and informant ratings differ, they display similar results when focusing on factors associated with quality of life, life satisfaction and well-being. Either self- or informant ratings may offer a reasonable source of information about people with dementia in terms of understanding associated factors.
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http://dx.doi.org/10.1093/ageing/afz177DOI Listing
April 2020

Use and costs of services and unpaid care for people with mild-to-moderate dementia: Baseline results from the IDEAL cohort study.

Alzheimers Dement (N Y) 2019 31;5:685-696. Epub 2019 Oct 31.

REACH: The Centre for Research in Ageing and Cognitive Health, University of Exeter, Exeter, UK.

Introduction: We examined 3-month service use and costs of care for people with mild-to-moderate dementia in Great Britain.

Methods: We analyzed Improving the experience of Dementia and Enhancing Active Life cohort study baseline data on paid care, out-of-pocket expenditure, and unpaid care from participants with dementia (N = 1547) and their carers (N = 1283). In regression analyses, we estimated per-group mean costs of diagnostic and sociodemographic subgroups.

Results: Use of services apart from primary and outpatient hospital care was low. Unpaid care accounted for three-quarters of total costs (mean, £4008 [standard error, £130] per participant). Most participants (87%) received unpaid care equating to 36 hours weekly. Estimated costs for people with Parkinson's dementia were £8609, £4359 for participants with mixed dementia, and £3484 for those with Alzheimer's disease. Total costs were lower for participants with dementia living alone than living with others (£2484 vs. £4360); costs were lower for female than for male participants (£3607 vs. £4272).

Discussion: Costs varied by dementia subtype, carer status, and living arrangement. Policy makers should recognize the high costs of unpaid care for people with dementia, who do not always get the support that they need or would like to receive.
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http://dx.doi.org/10.1016/j.trci.2019.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838500PMC
October 2019

The Genetic Links to Anxiety and Depression (GLAD) Study: Online recruitment into the largest recontactable study of depression and anxiety.

Behav Res Ther 2019 12 24;123:103503. Epub 2019 Oct 24.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, Denmark Hill, Camberwell, London, UK; UK National Institute for Health Research (NIHR) Biomedical Research Centre, South London and Maudsley Hospital, London, UK.

Background: Anxiety and depression are common, debilitating and costly. These disorders are influenced by multiple risk factors, from genes to psychological vulnerabilities and environmental stressors, but research is hampered by a lack of sufficiently large comprehensive studies. We are recruiting 40,000 individuals with lifetime depression or anxiety and broad assessment of risks to facilitate future research.

Methods: The Genetic Links to Anxiety and Depression (GLAD) Study (www.gladstudy.org.uk) recruits individuals with depression or anxiety into the NIHR Mental Health BioResource. Participants invited to join the study (via media campaigns) provide demographic, environmental and genetic data, and consent for medical record linkage and recontact.

Results: Online recruitment was effective; 42,531 participants consented and 27,776 completed the questionnaire by end of July 2019. Participants' questionnaire data identified very high rates of recurrent depression, severe anxiety, and comorbidity. Participants reported high rates of treatment receipt. The age profile of the sample is biased toward young adults, with higher recruitment of females and the more educated, especially at younger ages.

Discussion: This paper describes the study methodology and descriptive data for GLAD, which represents a large, recontactable resource that will enable future research into risks, outcomes, and treatment for anxiety and depression.
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http://dx.doi.org/10.1016/j.brat.2019.103503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891252PMC
December 2019

Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes.

Nat Genet 2019 08 31;51(8):1252-1262. Epub 2019 Jul 31.

Institute for Human Genetics, University of California, San Francisco, CA, USA.

Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform an integrative analysis of chromatin interactions, open chromatin regions and transcriptomes using promoter capture Hi-C, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing, respectively, in four functionally distinct neural cell types: induced pluripotent stem cell (iPSC)-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus-like neurons and primary astrocytes. We identify hundreds of thousands of long-range cis-interactions between promoters and distal promoter-interacting regions, enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several promoter-interacting regions by using clustered regularly interspaced short palindromic repeats (CRISPR) techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP and DRD2 are transcriptionally regulated by physically linked enhancers.
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http://dx.doi.org/10.1038/s41588-019-0472-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677164PMC
August 2019

Seasonal variation in salivary cortisol but not symptoms of depression and trait anxiety in pregnant women undergoing an elective caesarean section.

Psychoneuroendocrinology 2019 10 31;108:14-19. Epub 2019 May 31.

Biomedicine Division, School of Biosciences, Cardiff University, Cardiff, CF10 3AX, United Kingdom. Electronic address:

Objectives: Seasonal changes in mood and behaviour are commonly reported in the general population but considerably less is known regarding seasonality and pregnancy. This study investigated the relationship between seasons and depression and anxiety symptoms, salivary cortisol concentrations, custom birthweight centiles (CBWC) and placenta weight for pregnant women living in South Wales.

Methods: This study utilised data from the longitudinal Grown in Wales (GiW) cohort. Women were recruited at the presurgical elective caesarean section (ELCS) appointment, when they provided saliva samples and completed the Edinburgh Postnatal Depression Scale (EPDS) and trait subscale of the State-Trait Anxiety Inventory (STAI). Data on birthweight and placental weight was extracted from medical notes. Seasonal data was available for 316 participants.

Results: No association was identified between seasons and EPDS (p = .178), STAI scores (p = .544), CBWC (p = .683) or placental weight (p = .857). Significance was identified between seasons and salivary cortisol concentration (p<.001), with highest levels in autumn and winter. Adjusted linear regression identified spring (B=-.05, p=.007, 95% CI -.09, -.01) and summer (B=-.06, p = .001, 95% CI -09, -.02) compared to autumn, and spring (B=-.05, p=.009, 95% CI -.09, -.01) and summer (B=-.06, p=.002, 95% CI -.10, -.02) compared to winter to be associated with decreased cortisol concentrations.

Conclusion: This study found no association between season and maternally-reported mental health symptoms, birthweight by CBWC or placental weight but did between season and term salivary cortisol. This finding will have implications for studies that do not account for seasonality when using salivary cortisol as a biomarker.
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http://dx.doi.org/10.1016/j.psyneuen.2019.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854466PMC
October 2019

Professional autonomy and surveillance: the case of public reporting in cardiac surgery.

Sociol Health Illn 2019 07 15;41(6):1040-1055. Epub 2019 Mar 15.

Imperial College London, London, UK.

Professional autonomy has come under greater scrutiny due to managerialism, consumerism, information and communication technologies (ICT), and the changing composition of professions themselves. This scrutiny is often portrayed as a tension between professional and managerial logics. Recently, medical autonomy has increasingly been shaped in terms of transparency, where publication of clinical performance (via ICT) might be a more pervasive form of surveillance. Such transparency may have the potential for a more explicit managerial logic but is contested by clinicians. This paper applies notions of surveillance to public reporting of cardiac surgery, involving the online publication of mortality rates of named surgeons. It draws on qualitative data from a case-study of cardiac surgeons in one hospital, incorporating interviews with health care managers and national policymakers in England. We examine how managerial logics are mediated by professional autonomy, generating patterns of enrolment, resistance and reactivity to public reporting. The managerial 'gaze' of public reporting is becoming widespread but the surgical specialty is accommodating it, leading to a re-assertion of knowledge, based on professional definitions. The paper assesses whether this form of surveillance is challenging to or being assimilated by the medical profession, thereby recasting the profession itself.
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http://dx.doi.org/10.1111/1467-9566.12883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850054PMC
July 2019

A Comprehensive Model of Factors Associated With Subjective Perceptions of "Living Well" With Dementia: Findings From the IDEAL Study.

Alzheimer Dis Assoc Disord 2019 Jan-Mar;33(1):36-41

Wales Institute for Social and Economic Research, Data and Methods, Cardiff University, Cardiff.

Introduction: We aimed to better understand what predicts the capability to "live well" with dementia by identifying the relative contribution of life domains associated with the subjective experience of living well.

Methods: We analyzed data from 1547 individuals with mild-to-moderate dementia in the IDEAL cohort. We generated a "living well" latent factor from measures of quality of life, satisfaction with life, and well-being. We used multivariate modeling to identify variables related to living well measures and structural equation modeling to derive latent variables for 5 life domains and to examine the associations of these domains with living well.

Results: All 5 domains were individually associated with living well. When modeled together, the psychological characteristics and psychological health domain was the only independent predictor of living well [effect size, 3.55; 95% confidence interval (CI): 2.93-4.17], and effect sizes were smaller for physical fitness and physical health (1.23, 95% CI: -0.10 to 2.58), social capitals, assets and resources (0.67; 95% CI: -0.04 to 1.38), managing everyday life with dementia (0.33; 95% CI: -0.06 to 0.71), and social location (0.08; 95% CI: -2.10 to 2.26).

Discussion: Psychological resources, and the social, environmental, and physical factors that underpin positive psychological states, are potentially important targets for interventions and initiatives that aim to improve the experience of living with dementia.
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http://dx.doi.org/10.1097/WAD.0000000000000286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416010PMC
March 2020

A Comprehensive Model of Factors Associated With Capability to "Live Well" for Family Caregivers of People Living With Mild-to-Moderate Dementia: Findings From the IDEAL Study.

Alzheimer Dis Assoc Disord 2019 Jan-Mar;33(1):29-35

Wales Institute for Social and Economic Research, Data, and Methods, Cardiff University, Cardiff.

Introduction: Understanding key influences on outcomes for caregivers of people with dementia is hampered by inconsistent conceptualization and measurement of outcomes and limited evidence about the relative impact of different variables. We aimed to address these issues.

Methods: We analyzed data from 1283 caregivers of community-dwelling individuals with mild-to-moderate dementia in the Improving the experience of Dementia and Enhancing Active Life cohort study. We generated a "living well" latent factor from measures of quality of life, satisfaction with life, and well-being. We used structural equation modelling to derive latent variables for 7 domains reflecting caregivers' perceptions of their personal resources and experiences, and to examine the associations with caregivers' perceptions of their capability to "live well."

Results: The domain of psychological characteristics and psychological health was most strongly related to living well [2.53; 95% confidence interval (CI), 2.08-2.97], followed by physical fitness and physical health (1.48; 95% CI, 1.04-1.91) and experiencing caregiving (1.34; 95% CI, 0.99-1.70). Social capitals, assets and resources (0.68; 95% CI, 0.35-1.00) and relationship with the person with dementia (-0.22; 95% CI, -0.41 to -0.03) had smaller, significant associations. Social location (0.28; 95% CI, -0.33 to 0.89) and managing everyday life with dementia (0.06; 95% CI, -0.15 to 0.28) were not significantly associated with living well.

Discussion: These findings demonstrate the importance of supporting caregivers' psychological and physical health and their ability to develop and maintain positive coping strategies, as well as enabling them to maintain vital social capitals, assets and resources.
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http://dx.doi.org/10.1097/WAD.0000000000000285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416095PMC
March 2020

Protocol for the IDEAL-2 longitudinal study: following the experiences of people with dementia and their primary carers to understand what contributes to living well with dementia and enhances active life.

BMC Public Health 2018 Oct 30;18(1):1214. Epub 2018 Oct 30.

Alzheimer's Society Centre of Excellence, Centre for Research in Ageing and Cognitive Health (REACH), College of Medicine and Health, South Cloisters, St Luke's Campus, Exeter, EX1 2LU, UK.

Background: There is a major need for longitudinal research examining the experiences of people with dementia and their primary carers, as relatively little is known about how the factors associated with capability to 'live well' vary over time. The main aim of the IDEAL-2 study is to investigate how and why, over time, people with dementia and their primary carers might vary in their capability to live well with dementia, whilst exploring both their use of health and care services and their unmet needs.

Methods: IDEAL-2 will build on the Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort of 1547 people (who, at recruitment between July 2014 and July 2016, had mild-to-moderate dementia), and their 1283 primary carers in Great Britain. The existing cohort will be enriched with additional participants with mild-to-moderate dementia (and their primary carers where available and willing) from the following groups: people with rarer forms of dementia, and/or those who are ≥90 years or < 65 years of age at time of recruitment. We will assess the primary outcome, capability to live well with dementia, and the factors influencing it using questionnaires at yearly intervals for 3 years. Additionally, we will seek to link the cohort data with administrative data to obtain information about health service use. Some participants will be invited for in-depth face-to-face interviews. The cohort study will be supplemented by linked research focusing on: the co-production of new measures of living well; including the perspectives of people with advanced dementia living in residential care settings; including people with dementia from black, Asian, and minority ethnic groups; and understanding the experience of people living with undiagnosed dementia.

Discussion: IDEAL-2 will provide evidence about the key indicators of, and factors associated with, living well over the course of dementia and how these differ for particular subgroups. It will tell us which combinations of services and support are most beneficial and cost-effective. Moreover, the IDEAL-2 study will gather evidence from under-researched groups of people with dementia, who are likely to have their own distinct perceptions of living well.
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http://dx.doi.org/10.1186/s12889-018-6129-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208177PMC
October 2018

Persistence of anxiety symptoms after elective caesarean delivery.

BJPsych Open 2018 Sep 17;4(5):354-360. Epub 2018 Aug 17.

Professor, Biomedicine Division, School of Biosciences, Cardiff University, UK.

Background: In the UK, 11.8% of expectant mothers undergo an elective caesarean section (ELCS) representing 92 000 births per annum. It is not known to what extent this procedure has an impact on mental well-being in the longer term.

Aims: To determine the prevalence and postpartum progression of anxiety and depression symptoms in women undergoing ELCS in Wales.

Method: Prevalence of depression and anxiety were determined in women at University Hospital Wales (2015-16; = 308) through completion of the Edinburgh Postnatal Depression Scale (EPDS; ≥13) and State-Trait Anxiety Inventory (STAI; ≥40) questionnaires 1 day prior to ELCS, and three postpartum time points for 1 year. Maternal characteristics were determined from questionnaires and, where possible, confirmed from National Health Service maternity records.

Results: Using these criteria the prevalence of reported depression symptoms was 14.3% (95% CI 10.9-18.3) 1 day prior to ELCS, 8.0% (95% CI 4.2-12.5) within 1 week, 8.7% (95% CI 4.2-13.8) at 10 weeks and 12.4% (95% CI 6.4-18.4) 1 year postpartum. Prevalence of reported anxiety symptoms was 27.3% (95% CI 22.5-32.4), 21.7% (95% CI 15.8-28.0), 25.3% (95% CI 18.5-32.7) and 35.1% (95% CI 26.3-44.2) at these same stages. Prenatal anxiety was not resolved after ELCS more than 1 year after delivery.

Conclusions: Women undergoing ELCS experience prolonged anxiety postpartum that merits focused clinical attention.

Declaration Of Interest: None.
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http://dx.doi.org/10.1192/bjo.2018.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127961PMC
September 2018

Examining cognition across the bipolar/schizophrenia diagnostic spectrum.

J Psychiatry Neurosci 2018 07;43(4):245-253

From the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK (Lynham, Hubbard, Hamshere, Legge, Owen, Jones, Walters); and the College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK (Tansey).

Background: Cognitive impairments are well-established features of schizophrenia, but there is ongoing debate about the nature and degree of cognitive impairment in patients with schizoaffective disorder and bipolar disorder. We hypothesized that there is a spectrum of increasing impairment from bipolar disorder to schizoaffective disorder bipolar type, to schizoaffective disorder depressive type and schizophrenia.

Methods: We compared performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery between participants with schizophrenia ( = 558), schizoaffective disorder depressive type ( = 112), schizoaffective disorder type ( = 76), bipolar disorder ( = 78) and healthy participants ( = 103) using analysis of covariance with post hoc comparisons. We conducted an ordinal logistic regression to examine whether cognitive impairments followed the hypothesized spectrum from bipolar disorder (least severe) to schizophrenia (most severe). In addition to categorical diagnoses, we addressed the influence of symptom domains, examining the association between cognition and mania, depression and psychosis.

Results: Cognitive impairments increased in severity from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia and schizoaffective disorder depressive type. Participants with schizophrenia and schizoaffective disorder depressive type showed equivalent performance ( = 0.07, = 0.90). The results of the ordinal logistic regression were consistent with a spectrum of deficits from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia/schizoaffective disorder depressive type (odds ratio = 1.98, < 0.001). In analyses of the associations between symptom dimensions and cognition, higher scores on the psychosis dimension were associated with poorer performance (B = 0.015, standard error = 0.002, < 0.001).

Limitations: There were fewer participants with schizoaffective disorder and bipolar disorder than schizophrenia. Despite this, our analyses were robust to differences in group sizes, and we were able to detect differences between groups.

Conclusion: Cognitive impairments represent a symptom dimension that cuts across traditional diagnostic boundaries.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019354PMC
July 2018

Analysis of shared heritability in common disorders of the brain.

Science 2018 06;360(6395)

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
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http://dx.doi.org/10.1126/science.aap8757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097237PMC
June 2018

Examining cognition across the bipolar/schizophrenia diagnostic spectrum.

J Psychiatry Neurosci 2018 Apr 5;43(3):170076. Epub 2018 Apr 5.

From the MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK (Lynham, Hubbard, Hamshere, Legge, Owen, Jones, Walters); and the College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK (Tansey).

Background: Cognitive impairments are well-established features of schizophrenia, but there is ongoing debate about the nature and degree of cognitive impairment in patients with schizoaffective disorder and bipolar disorder. We hypothesized that there is a spectrum of increasing impairment from bipolar disorder to schizoaffective disorder bipolar type, to schizoaffective disorder depressive type and schizophrenia.

Methods: We compared performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery between participants with schizophrenia ( = 558), schizoaffective disorder depressive type ( = 112), schizoaffective disorder type ( = 76), bipolar disorder ( = 78) and healthy participants ( = 103) using analysis of covariance with post hoc comparisons. We conducted an ordinal logistic regression to examine whether cognitive impairments followed the hypothesized spectrum from bipolar disorder (least severe) to schizophrenia (most severe). In addition to categorical diagnoses, we addressed the influence of symptom domains, examining the association between cognition and mania, depression and psychosis.

Results: Cognitive impairments increased in severity from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia and schizoaffective disorder depressive type. Participants with schizophrenia and schizoaffective disorder depressive type showed equivalent performance ( = 0.07, = 0.90). The results of the ordinal logistic regression were consistent with a spectrum of deficits from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia/schizoaffective disorder depressive type (odds ratio = 1.98, < 0.001). In analyses of the associations between symptom dimensions and cognition, higher scores on the psychosis dimension were associated with poorer performance (B = 0.015, standard error = 0.002, < 0.001).

Limitations: There were fewer participants with schizoaffective disorder and bipolar disorder than schizophrenia. Despite this, our analyses were robust to differences in group sizes, and we were able to detect differences between groups.

Conclusion: Cognitive impairments represent a symptom dimension that cuts across traditional diagnostic boundaries.
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http://dx.doi.org/10.1503/jpn.170076DOI Listing
April 2018

Genome-wide significant locus for Research Diagnostic Criteria Schizoaffective Disorder Bipolar type.

Am J Med Genet B Neuropsychiatr Genet 2017 Dec 29;174(8):767-771. Epub 2017 Aug 29.

MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.

Studies have suggested that Research Diagnostic Criteria for Schizoaffective Disorder Bipolar type (RDC-SABP) might identify a more genetically homogenous subgroup of bipolar disorder. Aiming to identify loci associated with RDC-SABP, we have performed a replication study using independent RDC-SABP cases (n = 144) and controls (n = 6,559), focusing on the 10 loci that reached a p-value <10 for RDC-SABP in the Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder sample. Combining the WTCCC and replication datasets by meta-analysis (combined RDC-SABP, n = 423, controls, n = 9,494), we observed genome-wide significant association at one SNP, rs2352974, located within the intron of the gene TRAIP on chromosome 3p21.31 (p-value, 4.37 × 10 ). This locus did not reach genome-wide significance in bipolar disorder or schizophrenia large Psychiatric Genomic Consortium datasets, suggesting that it may represent a relatively specific genetic risk for the bipolar subtype of schizoaffective disorder.
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http://dx.doi.org/10.1002/ajmg.b.32572DOI Listing
December 2017

Women with bipolar disorder and pregnancy: factors influencing their decision-making.

BJPsych Open 2016 Sep 7;2(5):294-300. Epub 2016 Sep 7.

, MRCPsych, Section of Women's Mental Health, King's College London, UK.

Background: Women with bipolar disorder are at increased risk of having a severe episode of illness associated with childbirth.

Aims: To explore the factors that influence the decision-making of women with bipolar disorder regarding pregnancy and childbirth.

Method: Qualitative study with a purposive sample of women with bipolar disorder considering pregnancy, or currently or previously pregnant, supplemented by data from an online forum. Data were analysed using thematic analysis.

Results: Twenty-one women with bipolar disorder from an NHS organisation were interviewed, and data were used from 50 women's comments via the online forum of the UK's national bipolar charity. The centrality of motherhood, social and economic contextual factors, stigma and fear were major themes. Within these themes, new findings included women considering an elective Caesarian section in an attempt to avoid the deleterious effects of a long labour and loss of sleep, or trying to avoid the risks of pregnancy altogether by means of adoption or surrogacy.

Conclusions: This study highlights the information needs of women with bipolar disorder, both pre-conception and when childbearing, and the need for improved training for all health professionals working with women with bipolar disorder of childbearing age to reduce stigmatising attitudes and increase knowledge of the evidence base on treatment in the perinatal period.

Declaration Of Interest: None.

Copyright And Usage: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.
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http://dx.doi.org/10.1192/bjpo.bp.116.003079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013258PMC
September 2016

Is sleep disruption a trigger for postpartum psychosis?

Br J Psychiatry 2016 05;208(5):409-11

Katie J. S. Lewis, BSc, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University; Russell G. Foster, BSc, PhD, FRS, Sleep and Circadian Neuroscience Institute, Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford; Ian R. Jones, MRCPsych, PhD, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK

An episode of postpartum psychosis can be devastating for a woman and her family, and it is vital we understand the factors involved in the aetiology of this condition. Sleep and circadian rhythm disruption is a plausible candidate but further research is needed that builds on the latest advances in chronobiology and neuroscience.
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http://dx.doi.org/10.1192/bjp.bp.115.166314DOI Listing
May 2016

The Agewell trial: a pilot randomised controlled trial of a behaviour change intervention to promote healthy ageing and reduce risk of dementia in later life.

BMC Psychiatry 2015 Feb 19;15:25. Epub 2015 Feb 19.

North Wales Organisation for Randomised Trials in Health, Bangor University, Bangor, UK.

Background: Lifestyle factors represent prime targets for behaviour change interventions to promote healthy ageing and reduce dementia risk. We evaluated a goal-setting intervention aimed at promoting increased cognitive and physical activity and improving mental and physical fitness, diet and health.

Methods: This was a pilot randomised controlled trial designed to guide planning for a larger-scale investigation, provide preliminary evidence regarding efficacy, and explore feasibility and acceptability. Primary outcomes were engagement in physical and cognitive activity. Participants aged over 50 living independently in the community were recruited through a community Agewell Centre. Following baseline assessment participants were randomly allocated to one of three conditions: control (IC) had an interview in which information about activities and health was discussed; goal-setting (GS n = 24) had an interview in which they set behaviour change goals relating to physical, cognitive and social activity, health and nutrition; and goal-setting with mentoring (GM, n = 24) had the goal-setting interview followed by bi-monthly telephone mentoring. Participants and researchers were blinded to group assignment. Participants were reassessed after 12 months.

Results: Seventy-five participants were randomised (IC n = 27, GS n = 24, GM n = 24). At 12-month follow-up, the two goal-setting groups, taken together (GS n = 21, GM n = 22), increased their level of physical (effect size 0.37) and cognitive (effect size 0.15) activity relative to controls (IC n = 27). In secondary outcomes, the two goal-setting groups taken together achieved additional benefits compared to control (effect sizes ≥ 0.2) in memory, executive function, cholesterol level, aerobic capacity, flexibility, balance, grip strength, and agility. Adding follow-up mentoring produced further benefits compared to goal-setting alone (effect sizes ≥ 0.2) in physical activity, body composition, global cognition and memory, but not in other domains. Implementation of the recruitment procedure, assessment and intervention was found to be feasible and the approach taken was acceptable to participants, with no adverse effects.

Conclusions: A brief, low-cost goal-setting intervention is feasible and acceptable, and has the potential to achieve increased activity engagement.

Trial Registration: Current Controlled Trials ISRCTN30080637.
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http://dx.doi.org/10.1186/s12888-015-0402-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337106PMC
February 2015

Improving the experience of dementia and enhancing active life--living well with dementia: study protocol for the IDEAL study.

Health Qual Life Outcomes 2014 Nov 30;12:164. Epub 2014 Nov 30.

Department of Clinical Sciences, Brunel University, London, UK.

Background: Enabling people with dementia and carers to 'live well' with the condition is a key United Kingdom policy objective. The aim of this project is to identify what helps people to live well or makes it difficult to live well in the context of having dementia or caring for a person with dementia, and to understand what 'living well' means from the perspective of people with dementia and carers.

Methods/design: Over a two-year period, 1500 people with early-stage dementia throughout Great Britain will be recruited to the study, together with a carer wherever possible. All the participants will be visited at home initially and again 12 months and 24 months later. This will provide information about the way in which well-being, life satisfaction and quality of life are affected by social capitals, assets and resources, the challenges posed by dementia, and the ways in which people adjust to and cope with these challenges. A smaller group will be interviewed in more depth.

Discussion: The findings will lead to recommendations about what can be done by individuals, communities, health and social care practitioners, care providers and policy-makers to improve the likelihood of living well with dementia.
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http://dx.doi.org/10.1186/s12955-014-0164-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260182PMC
November 2014

The AgeWell study of behavior change to promote health and wellbeing in later life: study protocol for a randomized controlled trial.

Trials 2012 Jul 24;13:115. Epub 2012 Jul 24.

School of Psychology, Bangor University, Bangor, Gwynedd, LL57 2AS, UK.

Background: Lifestyle factors playing a role in the development of late-life disability may be modifiable. There is a need for robust evidence about the potential for prevention of disability through behavior change interventions.

Methods/design: This feasibility study involves the development, implementation and initial testing of a behavior change intervention in a naturalistic setting. A small-scale randomized controlled trial (RCT) will investigate the implementation of a goal-setting intervention aimed at promoting behavior change in the domains of physical and cognitive activity in the context of a community resource center for over-50s. Healthy older participants attending the center (n = 75) will be randomized to one of three conditions: control (an interview involving a general discussion about the center); goal-setting (an interview involving identification of up to five personal goals in the domains of physical activity, cognitive activity, diet and health, and social engagement); or goal-setting with mentoring (the goal-setting interview followed by bi-monthly telephone mentoring). All participants will be reassessed after 12 months. Primary outcomes are levels of physical and cognitive activity. Secondary outcomes address psychosocial (self-efficacy, mood, quality of life), cognitive (memory and executive function), and physical fitness (functional and metabolic) domains. Cost-effectiveness will also be examined.

Discussion: This study will provide information about the feasibility of a community-based lifestyle intervention model for over-50s and of the implementation of a goal-setting intervention for behavior change, together with initial evidence about the short-term effects of goal-setting on behavior.

Trial Registration: Current Controlled Trials ISRCTN30080637 (http://www.controlled-trials.com).
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http://dx.doi.org/10.1186/1745-6215-13-115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433386PMC
July 2012

Identification of high risk DISC1 protein structural variants in patients with bipolar spectrum disorder.

Neurosci Lett 2010 Dec 17;486(3):136-40. Epub 2010 Sep 17.

Department of Molecular Genetics, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, United States.

In a large Scottish pedigree, a balanced translocation t (1;11)(q42.1;q14.3) disrupting the DISC1 and DISC2 genes segregates with major mental illness, including schizophrenia and depression. A frame-shift carboxyl-terminal deletion was reported in DISC1 in an American family with schizophrenia, but subsequently found in two controls. Herein, we test one hypothesis utilizing a large scale case-control mutation analysis: uncommon DISC1 variants are associated with high risk for bipolar spectrum disorder. We have analyzed the regions of likely functional significance in the DISC1 gene in 504 patients with bipolar spectrum disorder and 576 ethnically similar controls. Five patients were heterozygous for ultra-rare protein structural variants not found in the 576 controls (p=0.02, one-sided Fisher's exact test) and shown to be ultra-rare by their absence in a pool of 10,000 control alleles. In our sample, ultra-rare (private) protein structural variants in DISC1 are associated with an estimated attributable risk of about 0.5% in bipolar spectrum disorder. These data are consistent with: (i) the high frequency of depression in the large Scottish family with a translocation disrupting DISC1; (ii) linkage disequilibrium analysis demonstrating haplotypes associated with relatively small increases in risk for bipolar disorder (<3-fold odds ratio). The data illustrate how low/moderate risk haplotypes that might be found by the HapMap project can be followed up by resequencing to identify protein structural variants with high risk, low frequency and of potential clinical utility.
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http://dx.doi.org/10.1016/j.neulet.2010.09.027DOI Listing
December 2010

Variation at the GABAA receptor gene, Rho 1 (GABRR1) associated with susceptibility to bipolar schizoaffective disorder.

Am J Med Genet B Neuropsychiatr Genet 2010 Oct;153B(7):1347-9

Department of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.

We have previously reported evidence that variation at GABA(A) receptor genes is associated with susceptibility to bipolar disorder with schizophrenia-like psychotic features (Research Diagnostic Criteria (RDC) schizoaffective disorder, bipolar type) with gene-wide significance at GABRB1, GABRA4, GABRB3, GABRA5, and GABRR3. Here we provide suggestive evidence implicating a sixth member of the gene family, GABRR1 (gene-wide P = 0.0058; experiment-wide corrected significance P = 0.052).
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http://dx.doi.org/10.1002/ajmg.b.31108DOI Listing
October 2010

Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia.

Arch Gen Psychiatry 2010 Apr;67(4):318-27

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, UK.

Context: Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date.

Objectives: To determine whether large (>100,000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia.

Design: A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray.

Setting: The Wellcome Trust Case Control Consortium.

Participants: There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents.

Main Outcome Measures: Overall load of CNVs and presence of rare CNVs.

Results: The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder.

Conclusions: Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder.
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http://dx.doi.org/10.1001/archgenpsychiatry.2010.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476027PMC
April 2010

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.

Nature 2010 Apr;464(7289):713-20

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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http://dx.doi.org/10.1038/nature08979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892339PMC
April 2010

The arterial supply of the patellar tendon: anatomical study with clinical implications for knee surgery.

Clin Anat 2009 Apr;22(3):371-6

Jack Brockhoff Reconstructive Plastic Surgery Research Unit, Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Victoria, Australia.

The middle-third of the patellar tendon (PT) is well-established as a potential graft for cruciate ligament reconstruction, but there is little anatomical basis for its use. Although studies on PT vascular anatomy have focused on the risk to tendon pedicles from surgical approaches and knee pathophysiology, the significance of its blood supply to grafting has not been adequately explored previously. This investigation explores both the intrinsic and extrinsic arterial anatomy of the PT, as relevant to the PT graft. Ten fresh cadaveric lower limbs underwent angiographic injection of the common femoral artery with radio-opaque lead oxide. Each tendon was carefully dissected, underwent plain radiography and subsequently schematically reconstructed. The PT demonstrated a well-developed and consistent vascularity from three main sources: antero-proximally, mainly by the inferior-lateral genicular artery; antero-distally via a choke-anastomotic arch between the anterior tibial recurrent and inferior medial genicular arteries; and posteriorly via the retro-patellar anastomotic arch in Hoffa's fat pad. Two patterns of pedicles formed this arch: inferior-lateral and descending genicular arteries (Type-I); superior-lateral, inferior-lateral, and superior-medial genicular arteries (Type-II). Both types supplied the posterior PT, with the majority of vessels descending to its middle-third. The middle-third PT has a richer intrinsic vascularity, which may enhance its ingrowth as a graft, and supports its conventional use in cruciate ligament reconstruction. The pedicles supplying the PT are endangered during procedures where Hoffa's fat pad is removed including certain techniques of PT harvest and total knee arthroplasty.
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http://dx.doi.org/10.1002/ca.20770DOI Listing
April 2009

Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.

Nat Genet 2008 Sep;40(9):1056-8

Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.
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http://dx.doi.org/10.1038/ng.209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703780PMC
September 2008
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